Abstract

Pharmacological activators of peroxisome proliferator-activated receptor-γ (PPARγ) inhibit growth of non-small-cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Because these agents engage off-target pathways, we have assessed the effects of PPARγ by overexpressing the protein in NSCLC cells. We reported previously that increased PPARγ inhibits transformed growth and invasiveness and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of cyclooxygenase-2 (COX-2) and produce high levels of prostaglandin E₂ (PGE₂). The goal of these studies was to identify the molecular mechanisms whereby PPARγ inhibits tumorigenesis. Increased PPARγ inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE₂ production. Suppression of COX-2 was mediated through increased activity of the tumor suppressor phosphatase and tensin homolog, leading to decreased levels of phospho-Akt and inhibition of nuclear factor-κB activity. Pharmacological inhibition of PGE₂ production mimicked the effects of PPARγ on epithelial differentiation in three-dimensional culture, and exogenous PGE₂ reversed the effects of increased PPARγ activity. Transgenic mice overexpressing PPARγ under the control of the surfactant protein C promoter had reduced expression of COX-2 in type II cells and were protected against developing lung tumors in a chemical carcinogenesis model. These data indicate that high levels of PGE₂ as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPARγ are mediated in part through blocking this pathway.